Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. It is a progressive disease that can affect individuals of any age, including children and young adults. By the time patients are diagnosed with this disease, the thickening of pulmonary arterial walls has often already developed. Increased resistance in pulmonary circulation places stain on the right ventricle (RV), which leads to right heart failure and death, with a mean overall survival of 2-3 years after diagnosis if untreated. The currently available therapies with vasodilators have only limited effects on the survival of these patients. Therefore, agents that eliminate excess pulmonary vascular cells have therapeutic potential due to their ability to reduce vascular wall thickness and thereby decrease pulmonary vascular resistance. In this regard, apoptosis-based therapies used to treat cancer may be useful for the treatment of PAH. Apoptotic agents, however, could also exert cardiotoxicity, which complicates the development of such a therapeutic approach for PAH patients with RVs that have been affected by pressure overload. My long-range goal is to develop apoptosis-based therapeutic strategies to reduce pulmonary vascular wall thickness without promoting cardiac cell death. The objective of this competing renewal application is to evaluate the effectiveness of apoptotic agents used for cancer therapy in reversing pulmonary vascular wall thickening and their effects on the RV using preclinical models of pulmonary hypertension. The central hypothesis is that cancer chemotherapeutic agents that promote programmed cell death can be used to reverse pulmonary vascular wall thickening without adversely affecting the hypertrophied RV under certain therapeutic conditions. This hypothesis has been formulated on the basis of preliminary data that have demonstrated that: (i) agents used in cancer chemotherapy, such as anthracyclines and proteasome inhibitors, reduce the thickness of pulmonary vascular walls in pulmonary hypertensive rats and mice, but not in normal animals; (ii) heart muscle cells and pulmonary vascular smooth muscle cells have different mechanisms of programmed cell death; and (iii) the hypertrophied RV has upregulated cell survival mechanisms. The rationale for the proposed research is that once an understanding of how cells are differentially killed in the pulmonary vasculature and the heart has been obtained, it will lead to new strategies to reduce pulmonary vascular wall thickness without affecting the heart. The objective of this application will be accomplished by pursuing two specific aims: 1) Identify the mechanism of the regression of pulmonary vascular wall thickening by apoptosis-based therapeutic agents; and 2) Define the effects of apoptosis-based therapeutic agents on the heart, including hypertrophied RV. The proposed work is innovative because it will investigate the mechanism of the reversal of pulmonary vascular wall thickening, address the issue of cardiotoxicity in the setting of affecting the pulmonary vasculature, fundamentally advance the knowledge of right heart biology that has been understudied to date, and provide novel mechanisms of cell death. These results will be significant because they are expected to provide new therapeutic strategies to treat patients with PAH.